Psoriasis is difficult to treat clinically and lacks an effective treatment. Low-molecular-weight heparin sodium (LMH) is an animal glycosaminoglycan with anti-inflammatory properties. Transdermal and intradermal retention studies have suggested that LMH sodium can reach the dermis. This study investigated the anti-psoriasis effects of LMH in an imiquimod-induced mouse model, examining pathological changes, inflammation levels, and protein expression. Transdermal application of LMH in imiquimod-induced psoriasis mice revealed that epidermal thickening and scaling were alleviated, as shown by PASI scores. Serum ELISA and real-time quantitative PCR showed that inflammatory factor levels and mRNA expression were reduced. This indicates that LMH inhibits P38 protein phosphorylation and ERK expression, blocking the MAPK pathway. Combining LMH with paeoniflorin further improved psoriasis symptoms in mice. These findings suggest that LMH has significant potential for clinical application in psoriasis treatment.